7. PROJECT SUMMARY/ABSTRACT Schizophrenia is one of the most disabling of all psychiatric conditions, and places significant burden on the individuals who experience the disorder, as well as their family members and society. Advances in pharmacotherapy and psychosocial interventions have led to significant reductions in hospitalization and psychotic symptoms, and have provided opportunities for affected individuals to become more integrated members of the community. Despite this significant progress, many individuals with schizophrenia remain markedly disabled by persistent negative symptoms, including lack of motivation, social withdrawal, emotional blunting, and poverty of speech. These negative symptoms are untreated by current pharmacotherapies and are notoriously unresponsive to existing interventions, leaving patients and family members with little to no options for treatment. Recently, there has been growing appreciation of the overlap between cognitive and negative symptoms in schizophrenia, and psychosocial studies of cognitive remediation have begun to show promise in treating negative symptoms by utilizing computer- and group-based exercises to enhance social and non-social cognition. We have preliminarily observed in post-hoc analyses of three separate randomized- controlled trials that Cognitive Enhancement Therapy (CET), an evidence-based cognitive remediation approach for schizophrenia, can result in significant reductions in broad negative symptom domains. Further, neurocognitive and social-cognitive improvement appear to underlie these symptom reductions, and point to the enhancement of cognition as one of the most promising approaches for treating negative symptoms in schizophrenia. To date, however, adequately designed trials of cognitive remediation interventions have yet to be conducted in patients with moderate-to-severe and persistent negative symptoms to confirm these effects. In response to RFA-MH-18-707, Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders, this project proposes to conduct a confirmatory efficacy trial to examine the efficacy of CET for the treatment of schizophrenia patients with significant and persistent negative symptoms. A total of 75 stabilized schizophrenia outpatients with moderate-to-severe persistent negative symptoms will be randomized to 18 months of CET or an active, enriched supportive therapy control. Comprehensive data on persistent negative symptoms, social and non-social cognition, and functional outcome will be collected prior to treatment and at frequent 6-month intervals to (1) confirm the efficacy of CET for improving persistent negative symptoms; (2) confirm the impact of cognitive target engagement on reduced negative symptoms; and (3) examine the short-term durability of CET effects on negative symptoms and functioning. The results of this project are expected to establish promising new avenues for the treatment of persistent negative symptoms in the condition, and to significantly reduce the personal and public health burden associated with schizophrenia.